Approximately 1.2 million people in the United States have type 1 diabetes (T1DM) and require insulin for survival. Half of these patients use an insulin pump, a subcutaneous insulin infusion (CSII) catheter, and rapid acting insulin to manage their diabetes. The other half of the patients inject insulin into their subcutaneous tissue 3 to 4 times per day (multiple dose injection therapy or MDI) using a syringe with a small gauge needle or an insulin pen. Most patients with type 1 diabetes SMBG (self-monitor blood glucose) multiple times per day using a glucose meter and test strips.
Although another 24 to 28 million people in the USA have type 2 diabetes (T2DM), only 2.5 million are currently being managed with insulin. The majority of patients with type 2 diabetes who manage with insulin conduct SMBG two or more times per day. Some patients with type 2 diabetes managed with diet, exercise, and oral medication SMBG daily. Further, the prevalence of type 2 diabetes is projected to increase to more than 60 million people by 2050 due to the epidemic of obesity, metabolic syndrome, and pre-diabetes in children and adolescence in the U.S. The number of people in the world with type 2 diabetes is expected to exceed 300 million by the year 2020. Patients with poorly controlled BG levels for months to years are at increased risk for MI, CHF, stroke, blindness, kidney failure, infection, limb amputation, and premature death. Aggressive BG control with insulin and oral hypoglycemia medications in elderly patients with type 2 diabetes has been associated with an increased risk for hypoglycemia and premature death. More than 50% of the T2DM patient managed with insulin could benefit from real-time CGM with alerts and alarms for hyperglycemia and hypoglycemia. Elderly patients with T2DM may have difficulty utilizing current subcutaneous tissue CGM glucose sensors that require self-insertion every 5 to 7 days and frequent SMBG prior to insulin dose adjustments.
Outcome studies have clearly demonstrated the clinical benefit of controlling the blood glucose (BG) concentration as close to normal for age throughout a person's lifetime. Even modest improvements in BG control lead to a marked reduction in the incidence of blindness, kidney failure, heart failure, neuropathy, and limb amputation due to micro-vascular disease. The combination of BG control, blood pressure control, and lipid lowering therapy leads to a marked reduction in the incidence of ischemic heart disease, myocardial infarction, peripheral vascular disease, and ischemic stroke due to macro-vascular disease.
Many people with T1DM are able to control their BG in the near-normal range using multiple dose injection (MDI) therapy or insulin pump therapy with rapid acting insulin delivered through a continuous subcutaneous insulin infusion (CSII) catheter. Safe and effective insulin therapy requires frequent BG monitoring to maintain the BG concentration in the desired range because human metabolism changes minute by minute due to the consumption of food (meal size, composition, and time of day), exercise (type, intensity and duration), illness, sleep, medications, and the complex interaction of hormones, cytokines, growth factors, and the brain/autonomic nervous system. Despite education and motivation, the majority of people with type 1 diabetes commonly experience clinically significant episodes of hyperglycemia, hypoglycemia, and glycemic variability.
A growing number of people with T1DM use the real-time glucose information from a subcutaneous tissue continuous glucose monitoring system (CGMS) to manage their blood glucose. After insertion into the subcutaneous tissue, the continuous glucose monitor (CGM or glucose sensor) measures and displays the interstitial fluid glucose concentration (mg/dL or mmol/L) once per minute for 5 to 7 days. People with T1DM can use the glucose trend information (direction and rate of change) and alarms to significantly improve their time in the desired target BG range (for example 90 to 140 mg/dl) and minimize the incidence and duration of hypoglycemia (for example <70 mg/dl). However, many children and adults do not utilize this new technology because the glucose sensors do not produce a measurement accurate enough to eliminate the need for a confirmatory fingerstick blood glucose measurement (SMBG) prior to making an adjustment in insulin therapy. Many glucose sensors do not correlate closely with BG measurements due to an unstable sensor-tissue interface, errors in calibration, variable time-lag, and sensor instability due to movement and bio-fouling.
Despite these limitations, CGM systems have been integrated with insulin pumps and control algorithms (closed-loop and semi-closed loop) to automatically adjust insulin delivery as part of an Artificial Pancreas (AP) System. Clinical research studies are currently evaluating the safety and efficacy of using real-time subcutaneous tissue CGM trend data to frequently adjust the subcutaneous tissue infusion of rapid acting insulin. The Medtronic Diabetes Revel System that integrates a real-time CGM with an insulin pump and a control algorithm recently received FDA approval for suspending the infusion of insulin for 2 hours at night when the CGM detects hypoglycemia.
Three continuous glucose monitoring systems are CE Mark approved in Europe as a tool for the management of type 1 diabetes in adults and children (Medtronic Diabetes, Abbott Diagnostics, and DexCom Inc.). The DexCom and Medtronic CGM glucose sensor have FDA approval for commercial sale in the U.S. The commercial CGMs are labeled as adjunctive devices that use the glucose trend information (direction and rate of change) to alert the patient of impending hyperglycemia and hypoglycemia. A reference blood glucose measurement is required multiple times per day to determine the appropriate doses of insulin and to calibrate the CGM sensor.
The CGM sensors have miniature flexible electrodes that are inserted through the skin into the subcutaneous adipose tissue every 5 to 7 days. The concentration of tissue fluid glucose is measured every 1 to 5 minutes using an enzyme-based electrochemical sensor that oxidizes glucose to hydrogen peroxide and extra electrons. The change in electric current is proportional to the change in the glucose concentration within the local environment around the sensor's electrodes. All CGM sensors require an initial calibration and frequent re-calibration (every 6 to 12 hours) over the 5 to 7 day life of the sensor using a reference blood glucose measurement.
CGM sensors commonly loose sensitivity and drift after implantation into the subcutaneous tissue due to the acute inflammatory response to injury. The environment surrounding the sensor's electrodes is filled with edema fluid, plasma proteins, thrombus, platelets, lysed cells, macrophages, and neutrophils. Many commercial CGM sensors do not correlate with the blood glucose concentration for several hours after implantation (run-in time 2 to 8 hours). Many commercial CGM sensors do not correlate with the blood glucose concentration during their entire 5 to 7 day lifetime due to ongoing changes in the tissue environment surrounding the sensor electrodes. The skin insertion site and subcutaneous tissue sensor site may develop an infection or more significant immune response if worn for more than 5 to 7 days. The adhesive tape used to hold the sensor to the skin commonly causes skin irritation and inflammation.
Several companies are trying to develop long-term implantable ISF or blood glucose monitoring systems. One company is developing a differential oxygen electrochemical CGM with telemetry for long-term implantation within the subcutaneous tissue of the abdomen. The CGM is designed to measure the concentration of subcutaneous tissue oxygen and glucose once per minutes for more than one year. The technology requires glucose and oxygen molecules to diffuse from the subcutaneous tissue through a fibrous capsule and porous membrane to interact with oxygen electrodes and oxygen electrodes covered with glucose-oxidase enzyme. The glucose responsive signal is subtracted from the oxygen signal to measure the glucose concentration. Accuracy, stability, longevity, and time-lag are adversely affected by slow and variable simple diffusion through the tissue, fibrous capsule, and membrane to the working electrode(s). This CGM may fail prematurely due to thickening and loss of capillaries within the fibrous capsule and chemical degradation of the enzymes/electrodes.
Another company is developing a CGM for long-term implantation within the subcutaneous tissue that monitors the concentration of ISF glucose using a glucose sensitive chemical (boronic acid) and fluorescent chemicals. The technology requires glucose molecules to diffuse from the subcutaneous tissue through a fibrous capsule and porous membrane to interact with the CGM chemicals. An external electronic/optical module is adhered to the skin to intermittently power the implanted glucose sensor and receive an output signal that correlates with a change in the intensity of florescence. Accuracy, stability, longevity, and time-lag are adversely affected by slow and variable simple diffusion of glucose molecules through the tissue, fibrous capsule, and membrane to the boronic acid. This CGM fails prematurely due to thickening and loss of capillaries within the fibrous capsule, degradation of the boronic acid, and photo-bleaching of the fluorescent chemicals.
A third company is developing a CGM for long-term implantation within the subcutaneous tissue that monitors the concentration of ISF glucose using glucose-sensitive fluorescent chemicals within a hydrogel. The hydrogel is designed to enhance the ingrowth and maintenance of vascular tissue. This technology requires glucose molecules to diffuse from the subcutaneous tissue through the hydrogel to interact with the fluorescent chemicals. An external electronic/optical module is adhered to the skin to intermittently send energy into the fluorescent chemicals and receive an output signal that correlates with a change in the intensity of florescence. Accuracy, stability, longevity, and time-lag are adversely affected by slow and variable simple diffusion of glucose molecules through the tissue and hydrogel. This CGM fails prematurely due to thickening and loss of capillaries within the hydrogel, degradation of the hydrogel, and photo-bleaching of the fluorescent chemicals.
Ultra-filtration is a commonly used clinical technique whereby the large molecules responsible for poor vascular sensor performance are excluded from the sample matrix. Ultrafiltration is accomplished by commercial membranes which are similar to those used for hemodialysis and hemofiltration. Current commercial membranes designed for short-term hemodialysis, hemo-filtration, and ultra-filtration have a relatively large and heterogeneous porous structure. Many of these membranes perform well for short periods of time, but may develop an obstructed fluid flow pathway due to the adhesion of protein, cells, platelets, and thrombus. For example, a wide variety of membranes (polysulfone, polyacrylonitrile (PAN), poly methyl-methacrylate, poly ether-sulfone, polyamide, ethyl-vinyl alcohol, polycarbonate, HEMA (hydroxyl methylmethacrylate), PMMA (polymethylmethacrylate), PHEMA (polyhydroxymethyl methacrylate), MM (methyl methacrylate), PE (polyethylene), HDE (high density polyethylene), PEG (polyethylene glycol), Sulfobetaine (polySB), silicone, PVC (poly vinyl chloride), PV (polyvinyl alcohol), PP (polypropylene), PEEK, polyamide (Nylon), cellulose diacetate, mixed-ester cellulose, PTFE (polytetrafluoroethylene-Teflon), acrylic copolymer; nanometer sized carbon nanotubes and polymer fibers (spun or weaved into an interconnecting mat-like structure), Dacron, PGA (polyglycolic acid), collagen (types I, III, IV, or V), elastin, fibrin, fibronectin, laminin, hyuronic acid, thrombin, and synthetic basement membrane (Matrigel) have been developed to facilitate a rapid rate of water flow/flux and the passage of small and large molecules (molecular cut-off 20,000 to <50,000 MW or Daltons) for short-term hemodialysis, hemo-filtration, and ultra-filtration.
Ultra-filtration is currently being used in clinical medicine during cardiopulmonary bypass and in volume overloaded ICU patients with renal disease to remove excess water from the body. The patient's blood is anti-coagulated with heparin and transported around the outside of the porous hollow fibers using the patient's arterial blood pressure or an external pump to produce flow. A small amount of vacuum can be applied to the inside of the porous membrane fibers to enhance ultra-filtrate formation. The anti-coagulated blood is returned to the patient's artery or vein. Sieving coefficient is calculated as the ratio of the concentration of the solute in the ultra-filtrate (glucose and water) to that in the incoming plasma (glucose and water). All of the commercial porous membranes have a sieving coefficient of 1 for glucose, which means all of the glucose molecules pass completely into the ultra-filtrate.
Many of these porous membranes have been commercialized for clinical use. However, none of the commercial porous membranes have been optimized for long-term implantation in the subcutaneous tissue or the bloodstream for the production of ultra-filtrate from tissue fluid or plasma with a small molecular weight cut-off.
No company, however, has been able to develop and commercialize a long-term glucose monitoring system, despite years of research and development. A long-term glucose monitoring system, such as one including a porous membrane for creation of an ultrafiltrate, is desired that overcomes some or all of the above challenges/obstacles.